Rapamycin derivatives for treating neuroblastoma

ABSTRACT

A rapamycin derivative for use in the treatment of neuroblastome, optionally in combination with a second drug substance.

The present invention relates to neuroblastoma treatment by use of rapamycin derivatives.

Rapamycin derivatives have been found to be useful e. g. as immunosuppressant, e. g. in the treatment of acute allograft rejection and have additionally potent antiproliferative properties which make them useful for cancer chemotherapy, particularly for the treatment of solid tumors, especially of advanced solid tumors.

Neuroblastoma is a disease in which malignant (cancer) cells form in nerve tissue of the adrenal gland, neck, chest, or spinal cord.

Neuroblastoma is the most common extracranial childhood cancer and the most common tumor occurring during infancy. It is an embryonal malignancy of the sympathetic nervous system arising from neuroblasts (pluripotent sympathetic cells). In the developing embryo, these cells invaginate, migrate along the neuraxis, and populate the sympathetic ganglia, adrenal medulla, and other sites, e.g. malignant (cancer) cells form in nerve tissue of the adrenal gland, neck, chest, or spinal cord.

Neuroblastoma often begins in the nerve tissue of the adrenal glands. There are two adrenal glands, one on top of each kidney in the back of the upper abdomen. The adrenal glands produce important hormones that help control heart rate, blood pressure, blood sugar, and the way the body reacts to stress. Neuroblastoma may also begin in the chest, in nerve tissue near the spine in the neck, or in the spinal cord.

Neuroblastoma most often begins during early childhood, usually in children younger than 5 years. It sometimes forms before birth but is usually found later, when the tumor begins to grow and cause symptoms.

Origin and migration pattern of neuroblasts during fetal development explains the multiple anatomic sites where these tumors occur; location of tumors appears to vary with age. Tumors can occur in the abdominal cavity (e.g. 40% adrenal, 25% paraspinal ganglia) or involve other sites (e.g. 15% thoracic, 5% pelvic, 3% cervical tumors, 12% miscellaneous). By the time neuroblastoma is diagnosed, the cancer has usually metastasized (spread), most often to the lymph nodes, bones, bone marrow, liver, and skin.

Most patients present with signs and symptoms related to tumor growth, although small tumors have been detected in infants on prenatal ultrasound. Large abdominal tumors often result in increased abdominal girth and other local symptoms (eg, pain). Paraspinal dumbbell tumors can extend into the spinal canal, impinge on the spinal cord, and cause neurologic dysfunction.

According to the present invention surprisingly it has been found that rapamycin derivatives are prone for the treatment of neuroblastomas and disorders associated therewith.

In one aspect the present invention provides:

1.1 A method for treating neuroblastomas, comprising administering to a subject in need thereof a therapeutically effective amount of a rapamycin derivative.

1.2 A method for inhibiting growth of neuroblastomas, comprising administering to a subject in need thereof a therapeutically effective amount of a rapamycin derivative.

1.3 A method for inducing neuroblastoma regression, e. g. tumor mass reduction, comprising administering to a subject in need thereof a therapeutically effective amount of a rapamycin derivative.

1.4 A method for treating neuroblastoma invasiveness or symptoms associated with neuroblastoma growth, comprising administering to ia subject in need thereof a therapeutically effective amount of a rapamycin derivative.

1.5 A method for preventing metastatic spread of neuroblastomas or for preventing or inhibiting growth of micrometastasis, comprising administering to a subject in need thereof a therapeutically effective amount of a rapamycin derivative.

1.6 A method for the treatment of a disease associated with neuroblastomas, comprising administering to a subject in need thereof a therapeutically effective amount of a therapeutically effective amount of a rapamycin derivative.

1.7 A method for inhibiting or controlling neuroblastomas, comprising administering to a subject in need thereof a therapeutically effective amount of a rapamycin derivative.

1.8 A method for enhancing the activity of a chemotherapeutic agent or for overcoming resistance to a chemotherapeutic agent against neuroblastomas, comprising administering to a subject in need thereof a therapeutically effective amount of a rapamycin derivative;

e.g. wherein a rapamycin derivative in 1.1 to 1.8 above is used preferably as a single active agent,

A method for treating neuroblastomas according to the present invention includes any method as defined under 1.2 to 1.8 above.

In another aspect the present invention provides

2.1 A rapamycin derivative for use for the treatment of neuroblastomas.

2.2 A rapamycin derivative for use for inhibiting growth of neuroblastomas.

2.3 A rapamycin derivative for use for inducing neuroblastoma regression, e. g. tumor mass reduction.

2.4 A rapamycin derivative for use for treating neuroblastoma invasiveness or symptoms associated with neuroblastoma growth.

2.5 A rapamycin derivative for use for preventing metastatic spread of neuroblastomas or for preventing or inhibiting growth of micrometastasis.

2.6 A rapamycin derivative for use for the treatment of a disease associated with neuroblastomas.

2.7 A rapamycin derivative for use for inhibiting or controlling.

2.8 A rapamycin derivative for use for enhancing the activity of a chemotherapeutic agent or for overcoming resistance to a chemotherapeutic agent against neuroblastomas;

e.g. wherein a rapamycin derivative in 2.1 to 2.8 above is used preferably as a single active agent,

A rapamycin derivative for use for the treatment of neuroblastomas according to the present invention includes any method as defined under 2.2 to 2.8 above.

In further aspects the present invention provides

3.1 A rapamycin derivative for use in the manufacture of a medicament for use in any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above.

3.2 The use of a rapamycin derivative for the manufacture of a medicament for use in any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above.

In a method or for use provided by the present invention a rapamycin derivative may be used, preferably, in the form of a pharmaceutical composition.

In another aspect the present invention provides

4.1 A pharmaceutical composition comprising a rapamycin derivative in association with at least one pharmaceutically acceptable excipient, e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrants, flow conditioners, lubricants, sugars or sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers; for use in any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above.

Neuroblastoma as used herein e.g. includes

-   tumors arising from the paraspinal sympathetic ganglia grown through     the spinal foramina into the spinal canal and impinging on the     spinal cord which may result in the presence of neurologic symptoms,     including weakness, limping, paralysis, and even bladder and bowel     dysfunction; -   thoracic neuroblastomas (posterior mediastinum) which may be     asymptomatic and usually are diagnosed by imaging studies obtained     for other reasons. Presenting signs or symptoms may be insignificant     and involve mild airway obstruction or chronic cough, leading to a     chest radiograph, -   thoracic tumors extending to the neck which can produce Horner     syndrome. Primary cervical neuroblastoma is rare but should be     considered in the differential diagnosis of masses of the neck,     especially in infants younger than 1 year with feeding or     respiratory difficulties; -   in a small proportion of infants younger than 6 months,     neuroblastoma presents with a small primary tumor and metastatic     disease confined to the liver, skin, and bone marrow. If this type     of tumor occurs in neonates, skin lesions may be confused with     congenital rubella, and, if the patient has severe skin involvement,     the term blueberry muffin may be used; -   a small number of patients present with opsoclonus and myoclonus a     paraneoplastic syndrome characterized by the presence of myoclonic     jerking and random eye movements.

The most common symptoms of neuroblastoma are caused by the tumor pressing on nearby tissues as it grows or by cancer spreading to the bone. Symptoms of neuroblastoma e.g. include lump in the abdomen (abdominal mass), neck, or chest, bulging eyes, uncontrolled eye movement caused by the tumor, swelling and bruising of the area around the eyes, caused by metastases (tumor spread), dark circles around the eyes (“black eyes”), bone pain, swollen stomach and breathing problems in infants, painless, bluish lumps under the skin in infants, weakness or paralysis (loss of ability to move a body part), e.g. present if there is spinal cord involvement, pain. Less common signs of neuroblastoma include e.g. fever, shortness of breath, feeling tired, easy bruising or bleeding (nemia or bruising may be present e.g. if there is bone marrow involvement), petechiae (flat, pinpoint spots under the skin caused by bleeding), high blood pressure, increased heart rate, severe watery diarrhea (compression of kidney or bladder by the tumor may cause changes in urination), diarrhea caused by a substance produced by the tumor (vasoactive intestinal peptide or VIP), jerky muscle movements, uncontrolled eye movement, swelling of the legs, ankles, feet, or scrotum.

Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a cancer is mentioned, also metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis is.

Rapamycin derivatives provided in a method or use according to the present invention include rapamycin substituted in position 40 and/or 16 and/or 32.

Such rapamycin derivatives include 40-0-alkyl-rapamycin derivatives, e.g. 40-O-hydroxyalkyl-rapamycin derivatives, for example 40-O-(2-hydroxy)-ethyl-rapamycin (everolimus),

rapamycin derivatives which are substituted in 40 position by heterocyclyl, e.g. 40-epi-(tetrazolyi)-rapamycin (also known as ABT578),

32-deoxo-rapamycin derivatives and 32-hydroxy-rapamycin derivatives, such as 32-deoxorapamycin,

16-O-substituted rapamycin derivatives such as 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R) -dihydro-rapamycin, or 16-pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin,

rapamycin derivatives which are acylated at the oxygen in position 40, e.g. 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin (also known as CCI779 or temsirolimus), rapamycin derivatives as disclosed in WO9802441 or WO0114387 (also sometimes designated as rapalogs), e.g. including AP23573, such as 40-O-dimethylphosphinyl-rapamycin,

compounds disclosed under the name biolimus (biolimus A9), including 40-O-(2-ethoxy)ethyl-rapamycin, and compounds disclosed under the name TAFA-93, AP23464, AP23675 or AP23841; or

rapamycin derivatives as e.g. disclosed in WO2004101583, WO9205179, WO9402136, WO9402385 and WO9613273.

A preferred rapamycin derivative provided in a method or use according to the present invention includes a compound of formula

e.g. including a compound of formula

wherein

R₁ is CH₃ or C₃₋₆alkynyl,

R₂ is H, —CH₂—CH₂—OH or —CH₂—CH₂—O—(C₁₋₈)alkyl, e.g. —CH₂—CH₂—O—CH₂—CH₃, and

X is ═O, (H, H) or (H, OH),

provided that R₂ is other than H when X is ═O and R₁ is CH₃,

or the compound ABT578, e.g. also designated as zotarolimus, the compound CCI779, e.g. also designated as temsirolimus, the compound AP23573 (from Ariad), e.g. 40-(dimethylphosphinyl)-rapamycin, or the compound TAFA-93 (from Isotechnika). A preferred rapamycin derivative provided in a method or use according to the present invention includeds a compound of formula I wherein R₁, R₂ and X iare as defined above, provided that R₂ is other than H when X is ═O and R₁ is CH₃,

A compound of formula I includes biolimus, such as biolimus-9, which is a compound of formula I wherein R₁ is methyl, X is ═O and R₂ is —CH₂—CH₂—O—CH₂—CH₃.

Preferred compounds of formula I include

40-O-(2-hydroxyethyl)-rapamycin, and/or

32-deoxorapamycin, and/or

16-pent-2-ynyloxy-32-deoxorapamycin, and/or

16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, and/or

16-pent-2-ynyloxy-32 (S or R)-dihydro-40-O-(2-hydroxyethyl)rapamycin, such as

40-O-(2-hydroxyethyl)-rapamycin and/or 32-deoxorapamycin,

e.g. 40-O-(2-hydroxyethyl)-rapamycin which is also known under the name everolimus.

Rapamycin derivatives provided in a method or use according to the present invention are also designated herein as “Compound(s) of (according to) the present invention”.

Any compound of the present invention may be used in any method, for any use and in any pharmaceutical composition as provided by the present invention, e.g. as defined under 1.1 to 1.8, 2.1 to 2.8, 3.1, 3.2 or 4. above, alone or in combination with one or more, at least one, second drug substance, e.g. wherein combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor, are excluded.

In other aspects the present invention provides

5.1 A combination of a compound of the present invention with at least one second drug substance, for any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above;

5.2 A pharmaceutical combination comprising a compound of the present invention in combination with at least one second drug substance, for any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above;

5.3 A pharmaceutical composition comprising a compound of the present invention in combination with at least one second drug substance and one or more pharmaceutically acceptable excipient(s), for any method or use as defined under for any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above;

5.4 The use of a compound of the present invention for the manufacture of a medicament for use in combination with a second drug substance, for use in any method or as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above;

5.5 A compound of the present invention in combination with at least one second drug substance for the manufacture of a medicament for use in any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above;

5.6 Any method as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above, comprising co-administering, concomitantly or in sequence, a therapeutically effective amount of a compound of the present invention and at least one second drug substance, e.g. in the form of a pharmaceutical combination or composition;

5.7 A method as defined under 5.6 above, wherein a compound of the present invention is administered intermittently;

e.g. wherein in 5.1 to 5.7 as defined above preferably combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor, are excluded.

Combinations include fixed combinations, in which a compound of the present invention, and at least one second drug substance are in the same formulation; kits, in which a compound of the present invention and at least one second drug substance in separate formulations are provided in the same package, e.g. with instruction for co-administration; and free combinations in which a compound of the present invention and at least one second drug substance are packaged separately, but instruction for concomitant or sequential administration are given.

In another aspect the present invention provides

5.8 A pharmaceutical package comprising a first drug substance which is a compound of the present invention and at least one second drug substance, beside instructions for combined administration;

5.9 A pharmaceutical package comprising a compound of the present invention beside instructions for combined administration with at least one second drug substance;

5.10 A pharmaceutical package comprising at least one second drug substance beside instructions for combined administration with a compound of the present invention; for use in any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above, e.g. including preferred aspects as defined above;

e.g. wherein in 5.8 to 5.10 as defined above preferably combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor, are excluded.

Treatment with combinations according to the present invention may provide improvements compared with single treatment.

In another aspect the present invention provides

5.11 A pharmaceutical combination comprising an amount of a compound of the present invention and an amount of a second drug substance, wherein the amounts are appropriate to produce a synergistic therapeutic effect;

5.12 A method for improving the therapeutic utility of a compound of the present invention comprising co-administering, e.g. concomitantly or in sequence, a therapeutically effective amount of a compound of the present invention and a second drug substance;

5.13 A method for improving the therapeutic utility of a second drug substance comprising co-administering, e.g. concomitantly or in sequence, a therapeutically effective amount of a compound of the present invention and a second drug substance.

for use in any method or use as defined under 1.1 to 1.8 or 2.1 to 2.8 above;

e.g. wherein in 5.11 to 5.13 as defined above preferably combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor, are excluded.

In a pharmaceutical combination, composition, package or method as defined under 5.1 to 5.13 above the activity of a compound of the present invention or a second drug substance may be enhanced compared with single treatment, e.g. combined treatment may result in synergistic effects or may overcome resistance against a compound of the present invention or a chemotherapeutic agent, e.g. when used in any method or use as defined under 1.1 to 1.8, or 2.1 to 2.8 above.

A (pharmaceutical) combination, package or composition, as defined under 5.1 to 5.13 comprises

a) a first agent which is a compound of the present invention and

b) a second drug substance as a co-agent which is a chemotherapeutic agent, e. g. as defined hereinafter or hereinbefore;

e.g. wherein combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor, are excluded.

Treatment as provided by the present invention includes prophylaxis (prevention). Disorders as used herein include diseases.

For such treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and the pharmacokinetic data of a compound used, the individual host, the mode of administration and the nature and severity of the conditions being treated. However, in general, for satisfactory results in larger mammals, for example humans, an indicated daily dosage includes a range

-   from about 0.0001 g to about 1.5 g, such as 0.001 g to 1.5 g; -   from about 0.001 mg/kg body weight to about 20 mg/kg body weight,     such as 0.01 mg/kg body weight to 20 mg/kg body weight,

for example administered in divided doses up to four times a day.

In a method, use, combination, pharmaceutical combination or pharmaceutical composition provided by the present invention a compound of the present invention may be administered as appropriate, e.g. in dosages which are known for compounds of the present invention, by any administration route, e.g. enterally, e.g. orally, or parenterally. E.g. everolimus may be administered, e.g. orally, in dosages from 0.1 mg up to 15 mg, such as 0.1 mg to 10 mg. e.g. 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg, more preferably from 0.5 mg to 10 mg, e.g. in the form of (dispersible) tablets; e.g. comprising everolimus in the form of a solid dispersion; e.g. a weekly dosage may include up to 70 mg, e.g. 10 to 70 mg, such as 30 to 50 mg, e.e. depending on the disease being treated. Other rapamycin derivatives of the present invention may be administered analogously, e.g. in similar dosage ranges.

A second drug substance may be administered in combination therapy as appropriate, e.g. according to a method as conventional, e.g. analogously to administration indications given for a specified drug for single treatment.

A second drug substance as used herein may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g. including intravenous, intraarterial, intramuscular, intracardiac, subcutanous, intraosseous infusion, transdermal (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane), inhalational administration; topically; e.g. including epicutaneous, intranasal, intratracheal administration; intraperitoneal (infusion or injection into the peritoneal cavity); epidural (peridural) (injection or infusion into the epidural space); intrathecal (injection or infusion into the cerebrospinal fluid); intravitreal (administration via the eye); or via medical devices, e.g. for local delivery, e.g. stents; e.g. in form of coated or uncoated tablets, capsules, (injectable) solutions, infusion solutions, solid solutions, suspensions, dispersions, solid dispersions; e.g. in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, or in the form of suppositories.

A second drug substance as used herein may be administered in the form of a pharmaceutically acceptable salt, or in free form; optionally in the form of a solvate. Pharmaceutical compositions according to the present invention may be manufactured according, e.g. analogously, to a method as conventional, e.g. by mixing, granulating, coating, dissolving or lyophilizing processes. Unit dosage forms may contain, for example, from about 0.1 mg to about 1500 mg, such as 1 mg to about 1000 mg.

Pharmaceutical compositions comprising a combination of the present invention and pharmaceutical compositions comprising a second drug substance as described herein, may be provided as appropriate, e.g. according, e.g. analogously, to a method as conventional, or as described herein for a pharmaceutical composition of the present invention.

By the term “second drug substance” as used herein is meant any chemotherapeutic agent other than a compound of the present invention, e.g. with the proviso that combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor, are excluded.

For example, a second drug substance as used herein includes e.g. anticancer drugs, anti-inflammatory and/or immunomodulatory and/or antiallergic drugs

For example, a second drug substance as used herein includes e.g. drugs which are useful in the treatment of neuroblastomas or symptoms associated therewith.

Anticancer drugs which are prone to be useful as a combination partner with a compound of the present invention, e.g. prone to be useful according to the present invention, e.g. include

i. a steroid; e.g. prednisone.

ii. an adenosine-kinase-inhibitor; which targets, decreases or inhibits nucleobase, nucleoside, nucleotide and nucleic acid metabolisms, such as 5-lodotubercidin, which is also known as 7H-pyrrolo[2,3-d]pyrimidin4-amine, 5-iodo-7-β-D-ribofuranosyl-(9CI).

iii. an adjuvant; which enhances the 5-FU-TS bond as well as a compound which targets, decreases or inhibits, alkaline phosphatase, such as leucovorin, levamisole.

iv. an adrenal cortex antagonist; which targets, decreases or inhibits the activity of the adrenal cortex and changes the peripheral metabolism of corticosteroids, resulting in a decrease in 17-hydroxycorticosteroids, such as mitotane.

v. an AKT pathway inhibitor; such as a compound which targets, decreases or inhibits Akt, also known as protein kinase B (PKB), such as deguelin, which is also known as 3H-bis[1]benzopyrano[3,4-b:6′,5′-e]pyran-7(7aH)-one, 13,13a-dihydro-9,10-dimethoxy-3,3-dimethyl-, (7aS, 13aS)-(9CI); and triciribine, which is also known as 1,4,5,6,8-pentaazaacenaphthylen-3-amine, 1,5-dihydro-5-methyl-1-β-D-ribofuranosyl; KP372-1 (QLT394),

vi. an alkylating agent; which causes alkylation of DNA and results in breaks in the DNA molecules as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA, such as chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, estramustine; nitrosueras, such as carmustine, fotemustine, lomustine, streptozocin (streptozotocin, STZ), BCNU; Gliadel; dacarbazine, mechlorethamine, e.g. in the form of a hydrochloride, procarbazine, e.g. in the form of a hydrochloride, thiotepa, temozolomide, nitrogen mustard, mitomycin, altretamine, busulfan, estramustine, uramustine. Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark CYCLOSTIN®; ifosfamide as HOLOXAN®, temozolomide as TEMODAR®, nitrogen mustard as MUSTARGEN®), estramustine as EMYCT®, streptozocin as ZANOSAR®.

vii. an angiogenesis inhibitor; which targets, decreases or inhibits the production of new blood vessels, e.g. which targets methionine aminopeptidase-2 (MetAP-2), macrophage inflammatory protein-1 (MIP-1alpha), CCL5, TGF-beta, lipoxygenase, cyclooxygenase, and topoisomerase, or which indirectly targets p21, p53, CDK2 and collagen synthesis, e.g. including fumagillin, which is known as 2,4,6,8-decatetraenedioic acid, mono[(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]oct-6-yl] ester, (2E,4E,6E,8E)-(9CI); shikonin, which is also known as 1,4-naphthalenedione, 5,8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-(9CI); tranilast, which is also known as benzoic acid, 2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]-(9CI); ursolic acid; suramin; bengamide or a derivative thereof, thalidomide, TNP-470.

viii. an anti-androgen; which blocks the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue, such as nilutamide; bicalutamide (CASODEX®), which can be formulated, e.g., as disclosed in U.S. Pat. No. 4,636,505.

ix. an anti-estrogen; which antagonizes the effect of estrogens at the estrogen receptor level, e.g. including an aromatase inhibitor, which inhibits the estrogen production, i. e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively,

e.g. including atamestane, exemestane, formestane, aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, letrozole, toremifene; bicalutamide; flutamide; tamoxifen, tamoxifen citrate; tamoxifen; fulvestrant; raloxifene, raloxifene hydrochloride. Tamoxifen may be e.g. administered in the form as it is marketed, e.g., NOLVADEX®; and raloxifene hydrochloride is marketed as EVISTA®. Fulvestrant may be formulated as disclosed in U.S. Pat. No. 4,659,516 and is marketed as FASLODEX®.

x. an anti-hypercalcemia agent; which is used to treat hypercalcemia, such as gallium (III) nitrate hydrate; and pamidronate disodium.

xi. an antimetabolite; which inhibits or disrupts the synthesis of DNA resulting in cell death, such as 6-mercaptopurine; cytarabine; fludarabine; flexuridine; fluorouracil; 5-fluorouracil(5-FU), floxuridine (5-FUdR), capecitabine; raltitrexed; methotrexate;

cladribine; gemcitabine; gemcitabine hydrochloride; thioguanine; 6-thioguanine, hydroxyurea; DNA de-methylating agents, such as 5-azacytidine and decitabine; edatrexate; folic acid antagonists such as pemetrexed. Capecitabine and gemcitabine can be administered e.g. in the marketed form, such as XELODA® and GEMZAR®.

xii. an apoptosis inducer; which induces the normal series of events in a cell that leads to its death, e.g. selectively inducing the X-linked mammalian inhibitor of apoptosis protein XIAP, or e.g. downregulating BCL-xL; such as ethanol, 2-[[3-(2,3-dichlorophenoxy)propyl]amino]-(9CI); gambogic acid; embelin, which is also known as 2,5-cyclohexadiene-1,4-dione, 2,5-dihydroxy-3-undecyl; arsenic trioxide (TRISENOX®).

xiii. an aurora kinase inhibitor; which targets, decreases or inhibits later stages of the cell cycle from the G2/M check point all the way through to the mitotic checkpoint and late mitosis; such as binucleine 2, which is also known as methanimidamide, N′-[1-(3-chloro4-fluorophenyl)4-cyano-1H-pyrazol-5-yl]-N,N-dimethyl-(9CI).

xiv. a Bruton's Tyrosine Kinase (BTK) inhibitor; which targets, decreases or inhibits human and murine B cell development; such as terreic acid.

xv. a calcineurin inhibitor; which targets, decreases or inhibits the T cell activation pathway, such as cypermethrin, which is also known as cyclopropanecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-,cyano(3-phenoxyphenyl)methyl ester (9CI); deltamethrin, which is also known as cyclopropanecarboxylic aci, 3-(2,2-dibromoethenyl)-2,2-dimethyl-(S)-cyano(3-phenoxyphenyl)methyl ester, (1R,3R)-(9CI); fenvalerate, which is also known as benzeneacetic acid, 4-chloro-α-(1-methylethyl)-,cyano(3-phenoxyphenyl)methyl ester (9CI); and Tyrphostin 8; but excluding cyclosporin or FK506.

xvi. a CaM kinase II inhibitor; which targets, decreases or inhibits CaM kinases;

constituting a family of structurally related enzymes that include phosphorylase kinase, myosin light chain kinase, and CaM kinases I-IV; such as 5-isoquinolinesulfonic acid, 4-[(2S)-2-[(5-isoquinolinylsulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperazinyl)propyl]phenyl ester (9CI); benzenesulfonamide, N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methyl]amino]methyl]phenyl]N-(2-hydroxyethyl)-4-methoxy-(9CI).

xvii. a CD45 tyrosine phosphatase inhibitor; which targets, decreases or inhibits dephosphorylating regulatory pTyr residues on Src-family protein-tyrosine kinases, which aids in the treatment of a variety of inflammatory and immune disorders; such as phosphonic acid, [[2-(4-bromophenoxy)-5-nitrophenyl]hydroxymethyl](9CI).

xviii. a CDC25 phosphatase inhibitor; which targets, decreases or inhibits overexpressed dephosphorylate cyclin-dependent kinases in tumors; such as 1,4-naphthalenedione, 2,3-bis[(2-hydroyethyl)thio]-(9CI).

xix. a CHK kinase inhibitor; which targets, decreases or inhibits overexpression of the antiapoptotic protein Bcl-2; such as debromohymenialdisine. Targets of a CHK kinase inhibitor are CHK1 and/or CHK2.

xx. a controlling agent for regulating genistein, olomucine and/or tyrphostins; such as daidzein, which is also known as 4H-1-benzopyran-4-one, 7-hydroxy-3-(4-hydroxyphenyl)-(9CI); Iso-Olomoucine, and Tyrphostin 1.

xxi. a cyclooxygenase inhibitor; e.g. including Cox-2 inhibitors; which targets, decreases or inhibits the enzyme cox-2 (cyclooxygenase-2); such as 1H-indole-3-acetamide, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-N-(2-phenylethyl)-(9CI); 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, e.g. celecoxib (CELEBREX®), rofecoxib (VIOXX®), etoricoxib, valdecoxib; or a 5-alkyl-2-arylaminophenylacetic acid, e.g., 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib; and celecoxib.

xxii. a cRAF kinase inhibitor; which targets, decreases or inhibits the up-regulation of E-selectin and vascular adhesion molecule-1 induced by TNF; such as 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one; and benzamide, 3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-(9CI). Raf kinases play an important role as extracellular signal-regulating kinases in cell differentiation, proliferation, and apoptosis. A target of a cRAF kinase inhibitor includes, but is not limited, to RAF1.

xxiii. a cyclin dependent kinase inhibitor; which targets, decreases or inhibits cyclin dependent kinase playing a role in the regulation of the mammalian cell cycle; such as N9-isopropyl-olomoucine; olomoucine; purvalanol B, which is also known as Benzoic acid, 2-chloro-4-[[2-[[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino]-9-(1-methylethyl)-9H-purin-6-yl]amino]-(9CI); roascovitine; indirubin, which is also known as 2H-indol-2-one, 3-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-dihydro-(9CI); kenpaullone, which is also known as indolo[3,2-d][1]benzazepin-6(5H)-one, 9-bromo-7,12-dihydro-(9CI); purvalanol A, which is also known as 1-Butanol, 2-[[6-[(3-chlorophenyl)amino]-9-(1-methylethyl)-9H-purin-2-yl]amino]-3-methyl-, (2R)-(9CI); indirubin-3′-monooxime. Cell cycle progression is regulated by a series of sequential events that include the activation and subsequent inactivation of cyclin dependent kinases (Cdks) and cyclins. Cdks are a group of serine/threonine kinases that form active heterodimeric complexes by binding to their regulatory subunits, cyclins. Examples of targets of a cyclin dependent kinase inhibitor include, but are not limited to, CDK, AHR, CDK1, CDK2, CDK5, CDK4/6, GSK3beta, and ERK.

xxiv. a cysteine protease inhibitor; which targets, decreases or inhibits cystein protease which plays a vital role in mammalian cellular turnover and apotosis; such as 4-morpholinecarboxamide,N-[(1S)-3-fluoro-2-oxo-1-(2-phenylethyl)propyl]amino]-2-oxo-1-(phenylmethyl)ethyl]-(9CI).

xxv. a DNA intercalator; which binds to DNA and inhibits DNA, RNA, and protein synthesis; such as plicamycin, dactinomycin.

xxvi. a DNA strand breaker; which causes DNA strand scission and results in inhibition of DNA synthesis, ininhibition of RNA and protein synthesis; such as bleomycin.

xxvii. an E3 Ligase inhibitor; which targets, decreases or inhibits the E3 ligase which inhibits the transfer of ubiquitin chains to proteins, marking them for degradation in the proteasome; such as N-((3,3,3-trifluoro-2-trifluoromethyl)propionyl)sulfanilamide.

xxviii. an endocrine hormone; which by acting mainly on the pituitary gland causes the suppression of hormones in males, the net effect being a reduction of testosterone to castration levels; in females, both ovarian estrogen and androgen synthesis being inhibited; such as leuprolide; megestrol, megestrol acetate.

xxix. compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers), such as compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF-related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 9702266, e.g. the compound of ex. 39, EP0564409, WO9903854, EP0520722, EP0566226, EP0787722, EP0837063, U.S. Pat. No. 5,747,498, WO9810767, WO9730034, WO9749688, WO9738983 and, especially, WO9630347, e.g. a compound known as CP 358774, WO9633980, e.g. a compound known as ZD 1839; and WO 9503283, e.g. a compound known as ZM105180, e.g including trastuzumab (HERCEPTIN®), cetuximab, iressa, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.1 1, E6.3 or E7.6.3, 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are e.g. disclosed in WO03013541, erlotinib, gefitinib. Erlotinib can be administered in the form as it is marketed, e.g. TARCEVA®, and gefitinib as IRESSA®, human monoclonal antibodies against the epidermal growth factor receptor including ABX-EGFR.

xxx. an EGFR, PDGFR tyrosine kinase inhibitor; such as EGFR kinase inhibitors including tyrphostin 23, tyrphostin 25, tyrphostin 47, tyrphostin 51 and tyrphostin AG 825; 2-propenamide, 2-cyano-3-(3,4-dihydroxyphenyl)-N-phenyl-(2E)-(9CI); tyrphostin Ag 1478; lavendustin A; 3-pyridineacetonitrile, α-[(3,5-dichlorophenyl)methylene]-, (αZ)-(9CI); an example of an EGFR, PDGFR tyrosine kinase inhibitor e.g. includes tyrphostin 46. PDGFR tyrosine kinase inhibitor including tyrphostin 46. Targets of an EGFR kinase inhibitor include guanylyl cyclase (GC-C) HER2, EGFR, PTK and tubulin.

xxxi. a farnesyltransferase inhibitor; which targets, decreases or inhibits the Ras protein; such as a-hydroxyfarnesylphosphonic acid; butanoic acid, 2-[[(2S)-2-[[(2S,3S)-2-[[(2R)-2-amino-3-mercaptopropyl]amino]-3-methylpentyl]oxy]-1-oxo-3-phenylpropyl]amino]-4-(methylsulfonyl)-,1-methylethyl ester, (2S)-(9cl); manumycin A; L-744,832 or DK8G557, tipifarnib (R115777), SCH66336 (lonafarnib), BMS-214662,

xxxii. a Flk-1 kinase inhibitor; which targets, decreases or inhibits Flk-1 tyrosine kinase activity; such as 2-propenamide, 2-cyano-3-[4-hydroxy-3,5-bis(1-methylethyl)phenyl]-N-(3-phenylpropyl)-(2E)-(9CI). A target of a Flk-1 kinase inhibitor includes, but is not limited to, KDR.

xxxiii. a Glycogen synthase kinase-3 (GSK3) inhibitor; which targets, decreases or inhibits glycogen synthase kinase-3 (GSK3); such as indirubin-3′-monooxime. Glycogen Synthase Kinase-3 (GSK-3; tau protein kinase 1), a highly conserved, ubiquitously expressed serine/threonine protein kinase, is involved in the signal transduction cascades of multiple cellular processes. which is a protein kinase that has been shown to be involved in the regulation of a diverse array of cellular functions, including protein synthesis, cell proliferation, cell differentiation, microtubule assembly/disassembly, and apoptosis.

xxxiv. a histone deacetylase (HDAC) inhibitor; which inhibits the histone deacetylase and which possess anti-proliferative activity; such as compounds disclosed in WO0222577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide and pharmaceutically acceptable salts thereof; suberoylanilide hydroxamic acid (SAHA); [4-(2-amino-phenylcarbamoyl)-benzyl]-carbamic acid pyridine-3-ylmethyl ester and derivatives thereof; butyric acid, pyroxamide, trichostatin A, oxamflatin, apicidin, depsipeptide; depudecin; trapoxin, HC toxin, which is also known as cyclo[L-alanyl-D-alanyl-(□S,2S)-□-amino-□-oxooxiraneoctanoyl-D-prolyl] (9CI); sodium phenylbutyrate, suberoyl bis-hydroxamic acid; Trichostatin A, BMS-27275, pyroxamide, FR-901228, valproic acid.

xxxv. a HSP90 inhibitor; which targets, decreases or inhibits the intrinsic ATPase activity of HSP90; degrades, targets, decreases or inhibits the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, e.g., 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin-related compounds; radicicol and HDAC inhibitors. Other examples of an HSP90 inhibitor include geldanamycin, 17-demethoxy-17-(2-propenylamino)-(9CI). Potential indirect targets of an HSP90 inhibitor include FLT3, BCR-ABL, CHK1, CYP3A5*3 and/or NQ01*2.

xxxvi. a I-kappa B-alpha kinase inhibitor (IKK); which targets, decreases or inhibits NF-kappaB, such as 2-propenenitrile, 3-[(4-methylphenyl)sulfonyl]-(2E)-(9CI).

xxxvii. an insulin receptor tyrosine kinase inhibitor; which modulates the activities of phosphatidylinositol 3-kinase, microtubule-associated protein, and S6 kinases; such as hydroxyl-2-naphthalenylmethylphosphonic acid, LY294002.

xxxviii. a c-Jun N-terminal kinase (JNK) kinase inhibitor; which targets, decreases or inhibits Jun N-terminal kinase; such as pyrazoleanthrone and/or epigallocatechin gallate. Jun N-terminal kinase (JNK), a serine-directed protein kinase, is involved in the phosphorylation and activation of c-Jun and ATF2 and plays a significant role in metabolism, growth, cell differentiation, and apoptosis. A target for a JNK kinase inhibitor includes, but is not limited to, DNMT.

xxxix a microtubule binding agent; which acts by disrupting the microtubular network that is essential for mitotic and interphase cellular function; such as vinblastine, vinblastine sulfate; vinca alkaloids, such as vincristine, vincristine sulfate; vindesine; vinorelbine; taxanes, such as docetaxel; paclitaxel; discodermolides; colchicine, epothilones and derivatives thereof, e.g. epothilone B or a derivative thereof. Paclitaxel is marketed as TAXOL®; docetaxel as TAXOTERE®; vinblastine sulfate as VINBLASTIN R.P®; and vincristine sulfate as FARMISTIN®. Also included are the generic forms of paclitaxel as well as various dosage forms of paclitaxel. Generic forms of paclitaxel include, but are not limited to, betaxolol hydrochloride. Various dosage forms of paclitaxel include, but are not limited to albumin nanoparticle paclitaxel marketed as ABRAXANE®; ONXOL®, CYTOTAX®. Discodermolide can be obtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also included are Epotholine derivatives which are disclosed in U.S. Pat. No. 6,194,181, WO98/0121, WO9825929, WO9808849, WO9943653, WO9822461 and WO0031247. Especially preferred are Epotholine A and/or B.

xI. a mitogen-activated protein (MAP) kinase-inhibitor; which targets, decreases or inhibits Mitogen-activated protein, such as benzenesulfonamide, N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methyl]amino]methyl]phenyl]N-(2-hydroxyethyl)-4-methoxy-(9CI). The mitogen-activated protein (MAP) kinases are a group of protein serine/threonine kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. They regulate several physiological and pathological cellular phenomena, including inflammation, apoptotic cell death, oncogenic transformation, tumor cell invasion, and metastasis.

xIi. a MDM2 inhibitor; which targets, decreases or inhibits the interaction of MDM2 and the p53 tumor suppressor; such as trans4-iodo, 4′-boranyl-chalcone.

xlii. a MEK inhibitor; which targets, decreases or inhibits the kinase activity of MAP kinase MEK; such as Nexavar® (sorafenib tosylate), butanedinitrile, bis[amino[2-aminophenyl)thio]methylene]-(9CI). A target of a MEK inhibitor includes, but is not limited to ERK. An indirect target of a MEK inhibitor includes, but is not limited to, cyclin D1.

xIiii: a matrix metalloproteinase inhibitor (MMP) inhibitor; which targets, decreases or inhibits a class of protease enzyme that selectively catalyze the hydrolysis of polypeptide bonds including the enzymes MMP-2 and MMP-9 that are involved in promoting the loss of tissue structure around tumors and facilitating tumor growth, angiogenesis, and metastasis such as actinonin, which is also known as butanediamide, N-4-hydroxy-N1-[(1S)-1-[[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-2-pentyl-, (2R)-(9CI); epigallocatechin gallate; collagen peptidomimetic and non-peptidomimetic inhibitors; tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat; and its orally-bioavailable analogue marimastat, prinomastat, metastat, neovastat, tanomastat, TAA211, BMS-279251, BAY 12-9566, MMI270B or MJ996. A target of a MMP inhibitor includes, but is not limited to, polypeptide deformylase.

xliv. a NGFR tyrosine-kinase-inhibitor; which targets, decreases or inhibits nerve growth factor dependent p140ctk tyrosine phosphorylation; such as tyrphostin AG 879. Targets of a NGFR tyrosine-kinase-inhibitor include, but are not limited to, HER2, FLK1, FAK, TrkA, and/or TrkC. An indirect target inhibits expression of RAF1.

xlv. a p38 MAP kinase inhibitor, including a SAPK2/p38 kinase inhibitor;

which targets, decreases or inhibits p38-MAPK, which is a MAPK family member, such as phenol, 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-(9CI). An example of a a SAPK2/p38 kinase inhibitor includes, but is not limited to, benzamide, 3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-(9CI). A MAPK family member is a serine/threonine kinase activated by phosphorylation of tyrosine and threonine residues. This kinase is phosphorylated and activated by many cellular stresses and inflammatory stimuli, thought to be involved in the regulation of important cellular responses such as apoptosis and inflammatory reactions.

xlvi. a p56 tyrosine kinase inhibitor; which targets, decreases or inhibits p56 tyrosine kinase, which is an enzyme that is a lymphoid-specific src family tyrosine kinase critical for T-cell development and activation; such as damnacanthal, which is also known as 2-anthracenecarboxaldehyde,9,10-dihydro-3-hydroxy-1methoxy-9,10-dioxo-(9CI), Tyrphostin 46. A target of a p56 tyrosine kinase inhibitor includes, but is not limited to, Lck. Lck is associated with the cytoplasmic domains of CD4, CD8 and the beta-chain of the IL-2 receptor, and is thought to be involved in the earliest steps of TCR-mediated T-cell activation.

xlvii. a PDGFR tyrosine kinase inhibitor; targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases (part of the PDGFR family), such as targeting, decreasing or inhibiting the activity of the c-Kit receptor tyrosine kinase family, especially inhibiting the c-Kit receptor. Examples of targets of a PDGFR tyrosine kinase inhibitor includes, but are not limited to PDGFR, FLT3 and/or c-KIT; such as tyrphostin AG 1296; tyrphostin 9; 1,3-butadiene-1,1,3-tricarbonitrile,2-amino4-(1H-indol-5-yl)-(9CI); N-phenyl-2-pyrimidine-amine derivative, e. g. imatinib, IRESSA®. PDGF plays a central role in regulating cell proliferation, chemotaxis, and survival in normal cells as well as in various disease states such as cancer, atherosclerosis, and fibrotic disease. The PDGF family is composed of dimeric isoforms (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD), which exert their cellular effects by differentially binding to two receptor tyrosine kinases. PDGFR-π and PDGFR-β have molecular masses of ˜170 and 180 kDa, respectively.

xlviii. a phosphatidylinositol 3-kinase inhibitor; which targets, decreases or inhibits PI 3-kinase; such as wortmannin, which is also known as 3H-Furo[4,3,2-de]indeno[4,5-h]-2-benzopyran-3,6,9-trione, 11-(acetyloxy)-1,6b,7,8,9a,10,11,11b-octahydro-1-(methoxymethyl)-9a, 11b-dimethyl-, (1S,6bR,9aS,11R,11bR)-(9CI); 8-phenyl-2-(morpholin4-yl)-chromen4-one; quercetin, quercetin dihydrate. PI 3-kinase activity has been shown to increase in response to a number of hormonal and growth factor stimuli, including insulin, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, colony-stimulating factor, and hepatocyte growth factor, and has been implicated in processes related to cellular growth and transformation. An example of a target of a phosphatidylinositol 3-kinase inhibitor includes, but is not limited to, Pi3K.

xlix. a phosphatase inhibitor; which targets, decreases or inhibits phosphatase; such as cantharidic acid; cantharidin; and L-leucinamide, N-[4-(2-carboxyethenyl)benzoyl]glycyl-L-α-glutamyl-(E)-(9CI). Phosphatase remove the phosphoryl group and restore the protein to its original dephosphorylated state. Hence, the phosphorylation-dephosphorylation cycle can be regarded as a molecular “on-off” switch.

I. a platinum agent; which contains platinum and inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules; such as carboplatin; cisplatin; oxaliplatin; cisplatinum; satraplatin and platinum agents such as ZD0473. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. CARBOPLAT®; and oxaliplatin as ELOXATIN®.

Ii. a protein phosphatase inhibitor, including a PP1 and PP2 inhibitor and a tyrosine phosphatase inhibitor; which targets, decreases or inhibits protein phosphatase. Examples of a PP1 and PP2A inhibitor include cantharidic acid and/or cantharidin. Examples of a tyrosine phosphatase inhibitor include, but are not limited to, L-P-bromotetramisole oxalate; 2(5H)-furanone,4-hydroxy-5-(hydroxymethyl)-3-(1-oxohexadecyl)-, (5R)-(9CI); and benzylphosphonic acid.

The term “a PP1 or PP2 inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits Ser/Thr protein phosphatases. Type I phosphatases, which include PP1, can be inhibited by two heat-stable proteins known as Inhibitor-1 (I-1) and Inhibitor-2 (I-2). They preferentially dephosphorylate a subunit of phosphorylase kinase. Type II phosphatases are subdivided into spontaneously active (PP2A), CA²⁺-dependent (PP2B), and Mg²⁺-dependent (PP2C) classes of phosphatases. The term “tyrosine phosphatase inhibitor”, as used here, relates to a compounds which targets, decreases or inhibits tyrosine phosphatase. Protein tyrosine phosphatases (PTPs) are relatively recent additions to the phosphatase family. They remove phosphate groups from phosphorylated tyrosine residues of proteins. PTPs display diverse structural features and play important roles in the regulation of cell proliferation, differentiation, cell adhesion and motility, and cytoskeletal function. Examples of targets of a tyrosine phosphatase inhibitor include, but are not limited to, alkaline phosphatase (ALP), heparanase, PTPase, and/or prostatic acid phosphatase.

Iii. a PKC inhibitor and a PKC delta kinase inhibitor: The term “a PKC inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits protein kinase C as well as its isozymes. Protein kinase C (PKC), a ubiquitous, phospholipid-dependent enzyme, is involved in signal transduction associated with cell proliferation, differentiation, and apoptosis. Examples of a target of a PKC inhibitor include, but are not limited to, MAPK and/or NF-kappaB. Examples of a PKC inhibitor include, but are not limited to, 1-H-pyrrolo-2,5-dione,3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-(9CI); bisindolylmaleimide IX; sphingosine, which is known as 4-octadecene-1,3-diol, 2-amino-, (2S,3R,4E)-(9CI); staurosporine, which is known as 9,13-Epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-Im]pyrrolo[3,4-j][1,7]benzodiazonin-1-one, staurosporine derivatives such as disclosed in EP0296110, e. g. midostaurin; 2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-, (9S,10R,11R,13R)-(9CI); tyrphostin 51; and hypericin, which is also known as phenanthro[1,10,9,8-opqra]perylene-7,14-dione, 1,3,4,6,8,13-hexahydroxy-10,11-dimethyl-, stereoisomer (6CI,7CI,8CI,9CI), UCN-01,safingol, BAY 43-9006, bryostatin 1, perifosine; limofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196. The term “a PKC delta kinase inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits the delta isozymes of PKC. The delta isozyme is a conventional PKC isozymes and is Ca²⁺-dependent. An example of a PKC delta kinase inhibitor includes, but is not limited to, Rottlerin, which is also known as 2-Propen-1-one, 1-[6-[(3-acetyl-2,4,6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-8-yl]-3-phenyl-, (2E)-(9CI).

Iiii. a polyamine synthesis inhibitor; which targets, decreases or inhibits polyamines spermidine; such as DMFO, which is also known as (−)-2-difluoromethylornithin; N1, N12-diethylspermine 4HCl. The polyamines spermidine and spermine are of vital importance for cell proliferation, although their precise mechanism of action is unclear. Tumor cells have an altered polyamine homeostasis reflected by increased activity of biosynthetic enzymes and elevated polyamine pools.

Iiv. a proteosome inhibitor; which targets, decreases or inhibits proteasome, such as aclacinomycin A; gliotoxin; PS-341; MLN 341; bortezomib; velcade. Examples of targets of a proteosome inhibitor include, but are not limited to, O(2)(−)-generating NADPH oxidase, NF-kappaB, and/or farnesyltransferase, geranyltransferase I.

Iv. a PTP1B inhibitor; which targets, decreases or inhibits PTP1B, a protein tyrosine kinase inhibitor; such as L-leucinamide, N-[4-(2-carboxyethenyl)benzoyl]glycyl-L-αglutamyl-,(E)-(9CI).

Ivi. a protein tyrosine kinase inhibitor including a SRC family tyrosine kinase inhibitor; a Syk tyrosine kinase inhibitor; and a JAK-2 and/or JAK-3 tyrosine kinase inhibitor; The term “a protein tyrosine kinase inhibitor”, as used herein, relates to a compound which which targets, decreases or inhibits protein tyrosine kinases. Protein tyrosine kinases (PTKS) play a key role in the regulation of cell proliferation, differentiation, metabolism, migration, and survival. They are classified as receptor PTKs and non-receptor PTKs. Receptor PTKs contain a single polypeptide chain with a transmembrane segment. The extracellular end of this segment contains a high affinity ligand-binding domain, while the cytoplasmic end comprises the catalytic core and the regulatory sequences. Examples of targets of a tyrosine kinase inhibitor include, but are not limited to, ERK1, ERK2, Bruton's tyrosine kinase (Btk), JAK2, ERK %, PDGFR, and/or FLT3. Examples of indirect targets include, but are not limited to, TNFalpha, NO, PGE2, IRAK, iNOS, ICAM-1, and/or E-selectin. Examples of a tyrosine kinase inhibitor include, but are not limited to, tyrphostin AG 126; tyrphostin Ag 1288; tyrphostin Ag 1295; geldanamycin; and genistein.

Non-receptor tyrosine kinases include members of the Src, Tec, JAK, Fes, Abl, FAK, Csk, and Syk families. They are located in the cytoplasm as well as in the nucleus. They exhibit distinct kinase regulation, substrate phosphorylation, and function. Deregulation of these kinases has also been linked to several human diseases.

The term “a SRC family tyrosine kinase inhibitor”, as used herein, relates to a compound which which targets, decreases or inhibits SRC. Examples of a SRC family tyrosine kinase inhibitor include, but are not limited to, PP1, which is also known as 1H-pyrazolo[3,4-d]pyrimidin-4-amine, 1-(1,1-dimethylethyl)-3-(1-naphthalenyl)-(9CI); and PP2, which is also known as 1H-Pyrazolo[3,4-d]pyrimidin-4-amine, 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-(9CI).

The term “a Syk tyrosine kinase inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits Syk. Examples of targets for a Syk tyrosine kinase inhibitor include, but are not limited to, Syk, STAT3, and/or STAT5. An example of a Syk tyrosine kinase inhibitor includes, but is not limited to, piceatannol, which is also known as 1,2-benzenediol, 4-[(1E)-2-(3,5-dihydroxyphenyl)ethenyl]-(9CI).

The term “a Janus (JAK-2 and/or JAK-3) tyrosine kinase inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits janus tyrosine kinase. Janus tyrosine kinase inhibitor are shown anti-leukemic agents with anti-thrombotic, anti-allergic and immunosuppressive properties. Targets of a JAK-2 and/or JAK-3 tyrosine kinase inhibitor include, but are not limited to, JAK2, JAK3, STAT3. An indirect target of an JAK-2 and/or JAK-3 tyrosine kinase inhibitor includes, but is not limited to CDK2. Examples of a JAK-2 and/or JAK-3 tyrosine kinase inhibitor include, but are not limited to, Tyrphostin AG 490; and 2-naphthyl vinyl ketone.

Compounds which target, decrease or inhibit the activity of c-Abl family members and their gene fusion products, e. g. include PD180970; AG957; or NSC 680410.

Ivii. a retinoid; which target, decrease or inhibit retinoid dependent receptors; such as isotretinoin, tretinoin, alitretinoin, bexarotene, e.g. including an agent which interact with retinoic acid responsive elements on DNA, such as isotretinoin (13-cis-retinoic acid).

Iviii. a RNA polymerase 11 elongation inhibitor; which targets, decreases or inhibits insulin-stimulated nuclear and cytosolic p70S6 kinase in CHO cells; targets, decreases or inhibits RNA polymerase II transcription, which may be dependent on casein kinase II; and targets, decreases or inhibits germinal vesicle breakdown in bovine oocytes; such as 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole.

Ivix. a serine/threonine kinase inhibitor; which inhibits serine/threonine kinases; such as 2-aminopurine, also known as 1H-purin-2-amine(9CI). An example of a target of a serine/threonine kinase inhibitor includes, but is not limited to, dsRNA-dependent protein kinase (PKR). Examples of indirect targets of a serine/threonine kinase inhibitor include, but are not limited to, MCP-1, NF-kappaB, elF2alpha, COX2, RANTES, IL8,CYP2A5, IGF-1, CYP2B1, CYP2B2, CYP2H1, ALAS-1, HIF-1, erythropoietin, and/or CYP1A1.

Ix. a sterol biosynthesis inhibitor; which inhibits the biosynthesis of sterols such as cholesterol; such as terbinadine. Examples of targets for a sterol biosynthesis inhibitor include, but are not limited to, squalene epoxidase, and CYP2D6.

Ixi. a topoisomerase inhibitor; including a topoisomerase I inhibitor and a topoisomerase II inhibitor. Examples of a topoisomerase I inhibitor include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecan and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (the compound designated as A1 in WO9917804); 10-hydroxycamptothecin acetate salt; etoposide; idarubicin hydrochloride; irinotecan hydrochloride; teniposide; topotecan, topotecan hydrochloride; doxorubicin; epirubicin, epirubicin hydrochloride; mitoxantrone, mitoxantrone hydrochloride; daunorubicin, daunorubicin hydrochloride, dasatinib (BMS-354825). Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR®. Topotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark HYCAMTIN®. The term “topoisomerase II inhibitor”, as used herein, includes, but is not limited to, the anthracyclines, such as doxorubicin, including liposomal formulation, e.g., CAELYX®, daunorubicin, including liposomal formulation, e.g., DAUNOSOME®, epirubicin, idarubicin and nemorubicin; the anthraquinones mitoxantrone and losoxantrone; and the podophillotoxines etoposide and teniposide. Etoposide is marketed as ETOPOPHOS®; teniposide as VM 26-BRISTOL®; doxorubicin as ADRIBLASTIN® or ADRIAMYCIN®; epirubicin as FARMORUBICIN® idarubicin as ZAVEDOS®; and mitoxantrone as NOVANTRON®.

Ixii. VEGFR tyrosine kinase inhibitor; which targets, decreases and/or inhibits the known angiogenic growth factors and cytokines implicated in the modulation of normal and pathological angiogenesis. The VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1 (FIt-1), VEGFR-2 (Flk-1, KDR), and VEGFR-3 (FIt-4)] play a paramount and indispensable role in regulating the multiple facets of the angiogenic and lymphangiogenic processes. An example of a VEGFR tyrosine kinase inhibitor includes 3-(4-dimethylaminobenzylidenyl)-2-indolinone. Compounds which target, decrease or inhibit the activity of VEGFR are especially compounds, proteins or antibodies which inhibit the VEGF receptor tyrosine kinase, inhibit a VEGF receptor or bind to VEGF, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO9835958, e. g.1-(4-chloroanilino)-4-(4-pyridylmethyl) phthalazine or a pharmaceutical acceptable salt thereof, e. g. the succinate, or in WO0009495, WO0027820, WO0059509, WO9811223, WO0027819 and EP0769947; e.g. those as described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp.14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al in Toxicologic Pathology, Vol. 27, no. 1, pp 14-21, 1999; in WO0037502 and WO9410202; Angiostatin, described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; Endostatin described by M. S. O'Reilly et al, Cell 88, 1997, 277-285;anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e. g. RhuMab (bevacizumab). By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity. an example of an VEGF-R2 inhibitor e.g. includes axitinib,

Ixiii. a gonadorelin agonist, such as abarelix, goserelin, goserelin acetate,

Ixiv. a compound which induce cell differentiation processes, such as retinoic acid, alpha-, gamma- or 8-tocopherol or alpha-, gamma- or 8-tocotrienol.

Ixv. a bisphosphonate, e.g. including etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.

Ixvi. a heparanase inhibitor which prevents heparan sulphate degradation, e. g. PI-88,

Ixvii. a biological response modifier, preferably alymphokine or interferons, e. g. interferon alpha,

Ixviii. a telomerase inhibitor, e. g. telomestatin,

Ixix. mediators, such as inhibitors of catechol-O-methyltransferase, e.g. entacapone,

Ixx: ispinesib, permetrexed (Alimta®), sunitinib (SUl 1248), diethylstilbestrol (DES), BMS224818 (LEA29Y),

Ixxi somatostatin or a somatostatin analogue, such as octreotide (Sandostatine or Sandostatin LAR®).

Ixxii. Growth Hormone-Receptor Antagonists, such as pegvisomant, filgrastim or pegfilgrastim, or interferon alpha.

Treatment in combination with an anticancer drug, such as indicated herein, may be associated with radiotherapy.

Anti-inflammatory and/or immunomodulatory drugs which are prone to be useful in combination with a compound of the present invention, e.g. prone to be useful according to the present invention, e.g. include

-   mediators, e.g. inhibitors, of calcineurin, e.g. cyclosporin A, FK     506; -   ascomycins having immuno-suppressive properties, e.g. ABT-281,     ASM981; -   corticosteroids; cyclophosphamide; azathioprene; leflunomide;     mizoribine; -   mycophenolic acid or salt; e.g. sodium, mycophenolate mofetil; -   15-deoxyspergualine or an immunosuppressive homologue, analogue or     derivative thereof; -   mediators, e.g. inhibitors, of bcr-abl tyrosine kinase activity; -   mediators, e.g. inhibitors, of c-kit receptor tyrosine kinase     activity; -   mediators, e.g. inhibitors, of PDGF receptor tyrosine kinase     activity, e.g. Gleevec (imatinib); -   mediators, e.g. inhibitors, of p38 MAP kinase activity, -   mediators, e.g. inhibitors, of VEGF receptor tyrosine kinase     activity, -   mediators, e.g. inhibitors, of PKC activity, e.g. as disclosed in     WO0238561 or WO0382859, e.g. the compound of Example 56 or 70; -   mediators, e.g. inhibitors, of JAK3 kinase activity, e.g.     N-benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide     α-cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (Tyrphostin AG 490),     prodigiosin 25-C (PNU156804),     [4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131),     [4-(3′-bromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline]     (WHI-P154), [4-(3′,     5′-dibromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline]     WHI-P97, KRX-211,     3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile,     in free form or in a pharmaceutically acceptable salt form, e.g.     mono-citrate (also called CP-690,550), or a compound as disclosed in     WO2004052359 or WO2005066156; -   mediators, e.g. agonists or modulators of S1P receptor activity,     e.g. FTY720 optionally phosphorylated or an analog thereof, e.g.     2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol     optionally phosphorylated or     1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic     acid or its pharmaceutically acceptable salts; -   immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies     to leukocyte receptors, e.g., Blys/BAFF receptor, MHC, CD2, CD3,     CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86, IL6     receptor (e.g. tocilizumab), IL-12 receptor, IL-17 receptor, IL-23     receptor or their ligands; -   other immunomodulatory compounds, e.g. a recombinant binding     molecule having at least a portion of the extracellular domain of     CTLA4 or a mutant thereof, e.g. an at least extracellular portion of     CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence,     e.g. CTLA4Ig (for ex. designated ATCC 68629) or a mutant thereof,     e.g. LEA29Y; or an anti-CTLA4 agent, such as ipilimumab: -   mediators, e.g. inhibitors of adhesion molecule activities, e.g.     LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or     VLA-4 antagonists, -   mediators, e.g. antagonists of CCR9 activity, -   mediators, e.g. inhibitors, of MIF activity, -   5-aminosalicylate (5-ASA) agents, such as sulfasalazine,     Azulfidine®, Asacol®, Dipentum®, Pentasa®, Rowasa®, Canasa®,     Colazal®, e.g. drugs containing mesalamine; e.g mesalazine in     combination with heparin; -   mediators, e.g. inhibitors, of TNF-alpha activity, e.g. including     antibodies which bind to TNF-alpha, e.g. infliximab (Remicade®),     thalidomide, lenalidomide, golimumab, adalimumab (Humira®, fully     human immunoglobulin G (IgG1) monoclonal antibody that is specific     for human TNF alpha), etanercept (Enbrel®)), certolizumab pegol     (Cimzia®, CDP 870), -   nitric oxide releasing non-steriodal anti-inflammatory drugs     (NSAIDs), e.g. including COX-inhibiting NO-donating drugs (CINOD); -   phospordiesterase, e.g. mediators, such as inhibitors of PDE4B     activity, -   mediators, e.g. inhibitors, of caspase activity, -   mediators, e.g. agonists, of the G protein coupled receptor GPBAR1, -   mediators, e.g. inhibitors, of ceramide kinase activity, -   ‘multi-functional anti-inflammatory’ drugs (MFAIDs), e.g. cytosolic     phospholipase A2 (cPLA2) inhibitors, such as membrane-anchored     phospholipase A2 inhibitors linked to glycosaminoglycans; -   antibiotics, such as penicillins, cephalosporins, erythromycins,     tetracyclines, sulfonamides, such as sulfadiazine, sulfisoxazole;     sulfones, such as dapsone; pleuromutilins, fluoroquinolones, e.g.     metronidazole, quinolones such as ciprofloxacin; levofloxacin;     probiotics and commensal bacteria e.g. Lactobacillus, Lactobacillus     reuteri; -   antiviral drugs, such as ribivirin, vidarabine, acyclovir,     ganciclovir, zanamivir, oseltamivir phosphate, famciclovir,     atazanavir, amantadine, didanosine, efavirenz, foscarnet, indinavir,     lamivudine, nelfinavir, ritonavir, saquinavir, stavudine,     valacyclovir, valganciclovir, civacir, zidovudine, -   mediators, e.g. inhibitors of the blood protein “complement 5a”,     such as pexelizumab, -   serum phosphorus controlling agents, e.g. sevelamer carbonate     (Renagel®), phosphate binders that reduces high serum phosphate     levels in renal disease patients, such as lanthanum carbonate     (Fosrenol®).

Anti-inflammatory drugs which are prone to be useful in combination with a compound of the present invention, e.g. prone to be useful according to the present invention, include e.g. non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); cyclooxygenase-2 (COX-2) inhibitors such as celecoxib; inhibitors of phosphodiesterase type IV (PDE-IV); antagonists of the chemokine receptors, especially CCR-1, CCR-2, and CCR-3; cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; anticholinergic agents such as muscarinic antagonists (ipratropium bromide); other compounds such as theophylline, sulfasalazine and aminosalicylates, e.g. 5-aminosalicylic acid and prodrugs thereof, antirheumatics.

Antiallergic drugs which are prone to be useful in combination with a compound of the present invention, e.g. prone to be useful according to the present invention, e.g. include antihistamines (H1-histamine antagonists), e.g. bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and non-steroidal anti-asthmatics such as β2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, salmeterol and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); bronchodilators, antiasthmatics (mast cell stabilizers).

A preferred chemotherapeutic drug in a method according to the present invention e.g. include

-   an alkylating agent, e.g. cyclophosphamide, ifosfamide, thiotepa,     melphalan, -   a platinum agent, e.g. carboplatin, cisplatin, -   a topoisomerase inhibitor, e.g. a topisomerase I inhibitor, such as     doxorubicin, etoposide; -   a microtubule binding agent;, e.g. including vincristine, -   a retinoid; e.g. isotretinoin (13-cis-retinoic acid), -   a Growth Hormone-Receptor Antagonists, e.g. filgrastim, -   an AKT pathway inhibitor; such as deguelin, KP372-1 (QLT394), -   a HSP90 inhibitor; e.g. geldanamycin, -   a Flk-1 kinase inhibitor; -   a tyrosine kinase receptor, -   a compound targeting, decreasing or inhibiting the activity of the     epidermal growth factor family of receptor tyrosine kinases (EGFR,     ErbB2).

Two or more combined compounds, e.g. a compound of the present invention and one or more chemotherapeutic agents, may be used together or sequentially.

Utility of compounds of the present invention, e.g. in combination with a second drug substance, for the treatment of neuroblastoma as hereinabove specified, may be demonstrated in vitro, in animal test methods as well as in clinic, e.g. by appropriate neuroblastoma cell line testing (apoptosis assay, cell proliferation assay and laser microdissection of neuroblasts in neuroblastoma tissue). Such assays are known, or may be provided as appropriate, e.g. according, e.g. analogously, to a method as conventional.

In each case where citations of patent applications or scientific publications are given, the subject-matter relating to the compounds is hereby incorporated into the present application by reference, e.g. comprised are likewise the pharmaceutical acceptable salts thereof, the corresponding racemates, diastereoisomers, enantiomers, tautomers as well as the corresponding crystal modifications of above disclosed compounds where present, e. g. solvates, hydrates and polymorphs, which are disclosed therein. The compounds used as active ingredients in the combinations of the invention may be prepared and administered as described in the cited documents or in the product description, respectively. Also within the scope of this invention is the combination of more than two separate active ingredients as set forth above, i. e. a pharmaceutical combination within the scope of this invention could include three active ingredients or more. Further, both the first agent and the co-agent are not the identical ingredient.

The structure of the drug substances identified by code numbers, generic or trade names may be taken from the Internet, actual edition of the standard compendium “The Merck Index” or from databases, e.g., Patents International, e.g., IMS World Publications, or the publications mentioned above and below. The corresponding content thereof is hereby incorporated by reference. 

1. A method for treating neuroblastomas, comprising administering to a subject in need thereof a therapeutically effective amount of a rapamycin derivative.
 2. (canceled)
 3. (canceled)
 4. A method according to claim 1, comprising said rapamycin derivative in association with at least one pharmaceutically acceptable excipient.
 5. A method according to claim 1, wherein said rapamycin derivative is used as a single active agent.
 6. A method according to claim 1 wherein said rapamycin derivative is combined with a second drug substance wherein combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor, are excluded.
 7. A pharmaceutical package comprising a rapamycin derivative and at least one second drug substance, and instructions for combined administration wherein combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor are excluded.
 8. A pharmaceutical package comprising a rapamycin derivative and instructions for combined administration with at least one second drug substance, wherein combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor are excluded.
 9. A pharmaceutical package comprising at least one second drug substance and instructions for combined administration with a rapamycin derivative, wherein combinations of a rapamycin derivative with an LFA-1 inhibitor, or MEK inhibitor and/or a tyrosine kinase inhibitor are excluded,
 10. A pharmaceutical package according to claim 7, 8, or 9 wherein a rapamycin derivative is selected from a compound of formula

wherein R₁ is CH₃ or C₃₋₆alkynyl, R₂ is H, —CH₂—CH₂—OH or —CH₂—CH₂—O—(C₁₋₆)alkyl, e.g. —CH₂—CH₂—O—CH₂—CH₃, and X is ═O, (H, H) or(H, OH), provided that R₂ is other than H when X is ═O and R₁ is CH₃, or the compound ABT578, e, the compound CC1779, the compound AP23573, or the compound TAFA-93. 